metabolism chemical transformaion of xenobiotics occurs in mostly in liver (enzymatic prosesses)...
TRANSCRIPT
Metabolism
•Chemical transformaion of xenobiotics
•Occurs in mostly in liver (enzymatic prosesses)
•Convertion into more hydrophil. subst. - excretion urine
•May convert pro-carciogenics into cytotox., muthagenic compounds
•Different persons may have differences in methabolism (genetic diff., physiol. factors)
•Methabolism of one xenobiotic may influence metab. of amother
Xenobiotics•Drugs•Other foreign non-essential compounds
Metabolism in non-hepatic tissue•Intestine mucosa•Kidney•Lung•Bacteria in GI-tract
First-pass metabolism:Xenobiotic metabolized before reachinggeneral circulation
Pathways of metabolism
Phase 1: Biotransformation
Attachment of new functional groups, transformation of exist. funct. groups
oxidation, reduction, hydroxylation, hydrolysis etc.
Phase 2: Conjugation.
Masking of an exist. funct. group by for instance
acetylation, glycosylation, attachment amino acid etc
More hydrophilic drug
Renal excretion
O OHHO
NCH3
Morphine
Demethylation
Phase 1 O OHHO
NH
Conjugationglucuronic acid
Phase 2 O OHO
NH
O OHCO2H
OHHO
Phase 1 react. not involving CYP450
microsome: Artefactual spherical particle, not present in the living cell, derived from pieces of the endoplasmic reticulum present in homogenates of tissues or cells: microsomes sediment from such homogenates when centrifuged at 100 000 g and higher: the microsomal fraction obtained in this way is often used as a source of mono-oxygenase enzymes.
Other microsomal enzymesAzoreductase
Nitroreductase
Flavinmonooxygenase-FMO (N and S-ox.)
Peroxidases
NN NH2
SO
OH2N
H2NNH2S
O
OH2N
Prontocil Sulfanilamide
R NO2 R NH2
Flavinmonooxygenase-FMOCont. FAD
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
OPO3 2-
Flavin mononucleotide
FMN
N
HN
NH
NHH3C
H3C
O
O
H OHOHOHH
H
OPO3 2-
FMNH2
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
O P OO
OH
O
OHO O
HO OH
N
N
N
N
NH2
FAD
N
HN
N
NHH3C
H3C
O
ORFADH2
Flavin adenine dinucleotide
N
N
N
NHH3C
H3C
O
O
H OHOHOHH
H
OH
Riboflavin(Vit B2)
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
O
NH2
N
N N
N
NH2
O
ORHO
OP
O
O
OH
P
OO
OHHO
N
O
HO
O
NH2
NADH
H H
Nicotinamid adenine dinucleotide
NADR=H
R=Phosphate: NADP+, NADPH
N
N N
N
NH2
O
OHHO
HO
Adenine(Vit. B4)
N
CO2H
Nicotinic acid / Niacin(Vit. B3)
Flavinmonooxygenase-FMO
N
N
N
NHH3C
H3C
O
OR
H2O
N
HN
N
NHH3C
H3C
O
OR
OH
N
HN
N
NHH3C
H3C
O
OR
OOH
FAD
Substrate Substrate-O
N
HN
NH
NHH3C
H3C
O
OR
FADH2
O2
NADPH
NADP+
RO
OH
NuPeroxidePeracid
O Nu
N-oxideSulfoxide
+ ROH
•Amine: ox. to N-oxide / hydroxylamine
•Sulfide: ox to sulfoxide , furter to sulfone
•Thiol:
Ox of soft Nu
R-SH R-S-S-R R-S-S-R
O
Non-microsomal enzymes•Enzymes in mitokondria•Enzymes in soubile tissue fractions
R-OH
prim or sec.
Alchohol dehydrogenase(NAD cont.)
aldehyde / ketoneR
O
H
Aldehyde dehydrogenaseR
O
OH
Alcohol dehydrogenase Aldehyde dehydrogenaseCH3OH HCO2HCH2O
SlowEtOH cometitive substr.
rel. fast
Tox. effects:AcidosisBlindness
HN
NH
NH
HN
O
O
NH
Tetrahydrofolate
NH
O CO2H
CO2H
HN
NH
NH
HN
O
O
N
NH
O CO2H
CO2H
OH
HCO2H
Dietary folic acid
10-Formyl-THF dehydrogenase
CO2
Non-microsomal enzymes (Phase 1)
Molybdenum Hydroxylases•Aldehyde oxidase•Xantine oxidase•Xantine dehydrogenase
Xanthine oxidaseElectron transfer: FAD - Fe2S2ˇI - Fe2S2ˇII - Moco - Substrate
Active form
Cont. Mo in cat. siteCont FAD and 2 Fe/s clustersUse H2O not O2
•Aldehyde oxidase
R H
O
R OH
O
N
Aza heterocycle
N OH NH
O
N
N N
N
H2N
AcO
AcO
FamciclovirAntiviral (Herpes etc)Pro-drug
Aldehyde oxidaseEsterase / hydrolysis HN
N N
N
H2N
HO
HO
O
Penciclovir
•Xantine oxidase•Xantine dehydrogenase
(requires NAD+)
xanthine oxidoreductase
HN
N
O
NH
N
Hypoxanthine
HN
NH
O
NH
N
Xanthine
O
HN
NH
O
NH
HN
Uric acid
OO
HN
N
O
NH
N
Allopurinol
HN
NH
O
NH
N
AlloxanthineInhib. enzyme
O
Treatment of gout (podagra)
Non-microsomal enzymes (Phase 1)
Oxidative deamination of amines•Monoamine oxidase (MAO)•Diamine oxidase (DAO)
R-CH2-NH2 + O2 [R-CH=NH] R-CHO + NH4+
NH
NH2
HO
Serotonin5-Hydroksotryptamin (5-HT)
MAO
NH
O
HO
Serotonine: •Neurotransmittor; temp. control, mood•Depresion: Low serotonine activity•MAO Inhibitors - Older antidepresants(low selectivity)
N NH
O O
Cl
MoklobemidAurorix® Moklobemid®
Other MAO substrates:
HN
OH
HO
HOH
Noradrenaline
NH2HO
HODopamine
Not MAO substrates (subst at α-C):
NH2
(S)-amfetaminLow dopamine conc. ≈ Parkinston
Active transport re-uptake transmittor(not Acetylcholine)
Non-selective monoamine re-uptake inhib.Tricyclic antidepressants
SSRI (selective serotonine re-uptake inhib.)“Lykkepiller” Prozac etc (Fontex)
NH2HO
HO
NH2HO
HO
OH
DA NE
HO
NH
NH2
5-HTα
β
β-Arylaminer
Y
X
RZ
N
αβ
β-Arylam
≈ β-Arylamin
Stor gruppe / sterisk hindingHindrer reopptak
O
F3C
NHH2N
Non-microsomal enzymes (Phase 1)
Oxidative deamination of amines•Monoamine oxidase (MAO)•Diamine oxidase (DAO)
Oxidize diamines, histamine NH2
HN
N
MAO like enzymes in plants
N
N NH
N
HN
BAPCYtokinin (Plant growth hormone)
N
N NH
N
NH2
O
+N
N NH
N N
N NH
N N
N NH
N
CK analogs, Anders Bråthe
Non-microsomal enzymes (Phase 1)
Miscellaneous react.
ReductionsS S RR R-SH
R-SO-R R-S-R (i.e.DMSO)
R-CO-R R-CHOH-R
R-NO-R R-NH-R
R-CH=CH-R R-CH2-CH2-R
R-OH R-H
Ar-OH Ar-H
β-Oxidation
R-CH2-CH2-CO2H R-CH2-CH2-CO-S-CoA R-CO2H
+
CHa-CO-S-CoA
Acetyl-CoA
R-CO-S-CoA
N
N N
N
NH2
O
OHPO3
OP
OP
O
HN
O OO OOH
O
HN
S
O
O
Acetyl-CoA
Nu
Hydrolysis - Esterases
O
ORR'
O
NRR'
R''
O
OHR
Esters as pro-drugs
Pathways of metabolism
Phase 1: Biotransformation
Attachment of new functional groups, transformation of exist. funct. groups
oxidation, reduction, hydroxylation, hydrolysis etc.
Phase 2: Conjugation.
Masking of an exist. funct. group by for instance
acetylation, glycosylation, attachment amino acid etc
More hydrophilic drug
Renal excretion
O OHHO
NCH3
Morphine
Demethylation
Phase 1 O OHHO
NH
Conjugationglucuronic acid
Phase 2 O OHO
NH
O OHCO2H
OHHO
Phase 2: Conjugation
Most comp. excreted as cojugates, ionic, hydrophilic groups added,
most common glucuronation
•Glucuronic acid conjugation•Sulfate conjugation•Conjugation with amino acids•Acetylation•Glutathione conjugation•Methylation
Phase 2: Conjugation
•Glucuronic acid conjugation
Substrates:
•Alchohols
•Phenols
•Amines
•Sulfides
•Carboxylic acids
•1,3-Dicarbonyls
O
HO
OHOHOH
OH
Glucose
O
CO2H
OHOOH
OH
UDP-Glucuronate
P P O
HO OH
N
N
O
O
RXH
O
CO2H
OHOH
OH
XR
RXH: Xenobiotic / Phase 1 metabolite
O
CO2H
OHOH
OH
XR
Kidney Urive excretion
Bile (galle)
RXH
O
CO2H
OHOH
OH
XR
IntestineRXH
Poor reabsorb.
O
CO2H
OHOH
OH
XR
Reabsorb
Entro-hepatic recyclingImportant for many hormones etc
O
CO2H
OHOOH
OH
UDP-Glucuronate
P P Uridine
OH
O
CO2H
OHOH
OH
OR
O
R
O
Relatively labile
Hydrolysis
OH R
O
HNu Macromolecule
Nu MacromoleculeR
O
Altered protein (hapten)Unwanted immune responce / allergic react.
Acyl migr.
ex. NSAIDs
Ar-NH2
Phase 1Ar-NH-OH Ar-NH-OH-Glu
UrinepH<7
Ar-NH-OH
H2O
Ar-N
Nitrene(c.f. carbene)
Bladder cancer
Phase 2: Conjugation
•Sulfate conjugation: Phenols, (alcohols, N-compounds)
ATPO NPO
O
OH
S
O
O
O
HO3P OH
PAPS
N
N
N
NH2HO
OS
O
O
O
•Conjugation with amino acids (Most ofthen Gly): Carboxylic acids
R-CO2H
O
R SCoA
H2N CO2H O
R NH
CO2H
No tox. conjugates known
Phase 2: Conjugation •Acetylation: N-compounds
O
H3C SCoANH N
O
•Glutathione conjugation: Electrophilic species
HS NH
HN
O CO2H
O
NH2
CO2HR-X + S NH
HN
O CO2H
O
NH2
CO2H
R
Glutathione conjugate
S OH
HN
O
O
R
Mercapturic acid der.
•Alkylhalides•Epoxides•Michael acceptors etc
may otherwisealkylate biomolecules
Br
BrRSH
Br
S
S R
Nu(i.e. DNA)
HN
O
OH
Paracetamol
Phase 1CYP450
H2O
N
O
O
HS-R
O
HN
O
SRH
HN
O
OH
SR
H2N Liver Protein
Liver dammage
Phase 2: Conjugation •Methylation (O and N- compd)
Prod. may be more lipophilic
React. mainly aimed at converting endogenic compouds
O.Metylation by COMT (catecol O-methyl transferase)
ATPO N
HO OH
N
N
N
NH2HO
OH3C
SAM (S-adenocyl methionine)
SH3C
CO2HH2N
HO
HO
SAM may also methylate N-comp.
HO
HO
OH
NH2
Noradrenaline(Norepinephrine)
MAO
HO
HO
OH
CHOAldehyde Dehydrogenase
HO
HO
OH
CO2H
COMT
HO
H3CO
OH
NH2
COMT
HO
H3CO
OH
CO2HMAO Aldehyde
Dehydrogenase
OH
NH2
EphedrineAdrenerg agonist
Conjugation react, in plant metabolism
N
N NH
N
HN
t-ZeatinCytokinin (Plant growth hormone)
N
N NH
N
NH2
OH
MAO likeenzynme
Not reversible, permanent inactivation
N
N NH
N
HN
OGlu
N
N N
N
HN
OH
Inactive storage forms
(Glu = Glucose)
N
N N
N
HN
OH
NH2
CO2H
alanine